Ammoniumaliphatic esters of carbamic acids



3,100,223 AMNIONIUMALDHATIC ETERS OF CARBAMIC ACIDS Thomas Robert Hopkins, Prairie Village, and James H.

This invention relates to a new series of quaternary ammonium compounds and to methods for their prepara tion. More particularly, this invention is concerned with quaternary ammonium alkyl carbarnates of the formula wherein R represents hydrogen, an aryl or substituted aryl radical, X is CH -CH CH=CH, or CEC-, M is a lower alkyl radical and Y is a therapeutically active salt anion.

Aryl radicals suitable as R substituents in the above general formula include the monoand di-nuclear aromatic carbocyclic aryl radicals such as phenyl, to-lyl or naphthyl. Substituents in these aromatic nuclei may be, for example, lower alkyl such as methyl, ethyl, propyl, butyl or pentyl; halo such as chloro, fluoro, iodo or bromo; amino, particularly tertiary amino, such as dilower alkyl amino for example, dimethyl, diethyl, or dibutylamino; or amino-lower alkoxy groups, for example dimethylaminoethoxy. Heterocyclic substituents on the aryl nuclei may be those containing from four to five carbon atoms, interrupted, if desired, by oxygen, nitrogen or sulfur linkages as for example, pyrrolidino, piperidino, morpholino, thiamorpholino, piperazino, etc. Substituents depicted by M in the above general formula may be lower alkyl radicals such as for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, etc.

The anion Y in the above formula is more particularly a therapeutically useful anion of an acid such as that of an inorganic acid for example a hydrohalic acid, i.e., hydrochloric, hydrobromic or hydriodic acid, sulphuric acid, phosphoric acid, nitric acid or thiocyanic acid; or an organic carboxylic acid such as, for example, acetic, acetoacetic, prop-ionic, beta-cyclopentylpropionic, oxalic, malonic, succinic, maleic, fuman'c, malic, citric, tartaric, benzoic, phenylacetic, beta-phenylpropionic, salicylic acid, acetylsal-icylic, or para-aminosalicylic acid; an organic sulphonic or sulphuric acid such as, for example, paratoluenesulphonic acid, methanesulphonic acid, ethanesulphonic acid, or methyl or ethyl sulphuric acid half ester. The anion Y may also be the bydroxyl ion.

The compounds of the present invention affect the autonomic nervous system and are therefore useful in reversing tensive states. For example, certain of the compounds stimulate autonornic ganglia and thereby raise the blood pressure from a hypotensive to a normal tensive level. Others depress autonomic ganglia and are useful in loweding blood pressure from hypertensive to normal tensive levels. For this purpose they may be administered orally or intraperitoneally. The dose may be varied widely depending upon the route of administration chosen, i.e., from five to one hundred milligrams per kilogram United States Patent ice body weight intnapenitoneally, or from about two to about twenty micrograms per kilogram body weight intravenously. The compounds may be formulated into preparations which contain these compounds in admixture with suitable pharmaceutical organic or inorganic, solid or liquid carriers appropriate for oral or parenteral administration. For this purpose, substances which may be employed are, for example, water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, cholesterol, or any other known carrier commonly used in the preparation of medicaments. The pharmaceutical preparations may be in the form of tablets, capsules or in liquid form such as solutions, suspensions or emulsions. If desired, they may contain auxiliary substances such as preserving agents, stabilizing agents, wetting agents, emulsifying agents, salts for varying osmotic pressure or buffers.

The novel quaternary ammonium alkyl carbamates are preparedby reacting a compound of the formula:

RNHCOOCH X-CHJ wherein the R and X substituents are as defined above and Z is a halogen, i.e., chloro or bromo with a tertiary amine, either in gaseous or liquid state, the latter form being preferably employed at ambient temperature. Alternatively, the novel carbamates may be prepared by reacting a compound of the formula:

wherein the R and X substituents are as defined above and M is hydrogen or lower alkyl, with a reactive ester of an alcohol such as those with strong inorganic acids, for example hydrohalic acids, e.g., hydrochloric, hydrobromic, hydriodic or sulphuric acid; with strong onganic sulphonic acids such as, for example, aryl sulphonic acids, e.g., para-toluenesulphonic, or alky-lsulphonic acids, e.g., methanesulphonic or ethanesulphonic acid, or with strong organic sulphuric acids, for example methyl or ethyl sulphuric acid halt ester. Further, preparation of the novel quaternary ammonium carbam-ates may be accomplished by reacting the appropriate 4-dialkylamino-2-alkynyl-N- (2-haloaryl) carbarnate with an alkyl halide.

The quaternizing reactions such as outlined above are performed according to standard procedures, that is to say, in the presence or absence of a solvent at room temperature or at :an elevated temperature or under cooling at atmospheric pressure or in a closed vessel under pressure. Suitable solvents are, more particularly, enzene, the lower alkanols such as methanol, ethanol, prop-anol, isopropanol or amyl alcohol or organic acid amides such as formamide or dimethylformamide. When reactive esters of hydroxylated lower hydrocarbon compounds are used as quaternizing agents, fonmamide or dimethylformamide may be used as solvents and the reaction is advantageously run in a closed vessel under pressure. Introduction of the amine into the starting material may be in the form of a gas or in the form of a liquid, whichever is appropriate.

Quaternary ammonium alkyl canbamates such as those obtained by the process of the invention may be converted into corresponding quaternary ammonium hydroxides, for example by reaction of the quaternary ammonium halides with silver oxide, or by reaction of the sulfates with barium hydroxide, or by treating the quatertherapeutically suitable quaternary ammonium salts by reaction with the acids, for example with inorganic acids such as hydrohalic acids, e.g., hydrochloric, hydrobromic or hydriodic, sulphuric, phosphoric acids, nitric acid or thiocyanic acid; or organic acids such as acetic, acetoa-cetic, propion-ic, di-lbeta-cyclopentylpropionic, oxalic, malonic, succinic, maleic, iumaric, malic, citric, tartaric, benzoic, phenylacetic, betaphenylpropionic, salicylic, acetylsalicylic or para-amino-salicylic acid; para-toluenesulphonic, methanesulphonic or ethanesulphonic acid. The

quaternary ammonium. salts obtained may also be converted into other quaternary salts directly without conversion into the quaternary hydroxide. For example, a quaternary ammonion iodide maybe reacted with freshly prepared silver chloride to yield the quaternary ammonium chloride.

Carbamates which are used as starting materials for the preparation of the novel quaternary ammonium compounds are fully described in the United States Patent No. 2,906,614, issued September 29, 1959, to Hopkins and Pullen and in J. Org. Chem. 24, 20402042 (1959).

The following examples are intended to illustrate but not to limit the scope of the present invention.

Example I 12.9 parts by weight of 4-chloro-2butynyl-N-(2-chlorohenyDcarbamate is dissolved in 200 parts by volume of benzene. Trimethyl-amine gas is passed slowly into the solution for about three hours. The solid precipitate which forms is removed by filtration and recrystallized from an ethanol-ether mixture. 9.1 parts by weight of 4-'[N-(2-ehlorophenyl) carbarnoyloxy]-2-butynyl-trimethylammonium chloride is obtained. Analysis.-Ca1cu.lated for C H Cl N O Ionic Cl, 11.22. Found, 11.28.

Example [I 20.8 parts by weight of 4-chloro-2-butenyl-N-(3-chloropheny1)carb=amate, 150 parts by volume of benzene and 15.2 parts by weight of triethylamine is stirred at ambient temperature for about forty hours. The precipitate which forms is removed by filtration and dried in a desiccator over P A total of 11.5 parts by weight of 4-[N-(3- chlorophenyhcarbamoyloxy] -2 butenyl triethylammonium chloride is obtained. Analysis-Calculated for C H CI N O C, 56.6, H, 7.3; N, 7.7; C1. 19.6; ionic Cl, 9.82. Found: C, 56.8; H, 7.02; N, 7.74; Cl, 19.5; Ionic Cl, 9.26.

Example III A mixture of 16 parts by weight of 4-dietl1y1amino-2- butynyl-N-(Z-chlorophenyl)carbamate, 16.35 parts of ethyl bromide and 250 parts by volume of benzene is mixed and stirred at ambient temperature for forty hours. The precipitate which forms is removed by filtration and dried under reduced pressure over P 0 A total of 5.7 parts by weight of 4-[N-(Z-chlorophenyDcarbamoyloxy] -2 butynyl-trielthylammonium bromide is obtained. Analysis-Calculated for CHHMBI'CINZOZ. Ionic Br, 19.77. Found, 19.62.

Example IV culated, 29.1. Found, 29.0.

4 The compounds listed below have been prepared by methods described in Examples 1, II, III and IV hereinabove, the designations shown as A, B, C and D corresponding to Examples 1, II, III and IV, respectively.

Example V to Example XVIII Analyses (ionic halide) Compound Method Found Caled.

flN-( l-chlorophenyl) earbarnoyloxyl- B 9. E7 9. 87

2:3utynyl triethylammonium chlon e.

t-carbamoyloxy-Z-butynyl triethyl B 14.17 14. 20

ammonium chloride.

4-(N-phenylcarbamoyloxy) -2-butenyl B 10. 10. 84

triothylammonium chloride.

4-[N-(3-cl1lor0phenyl)carbamoyloxyl- B 7.37 7. 97

2igutyny1 tributylarnmonium chlor e.

4-[I I-(3-ch1oropheny1) carbamoyloxyl- B 9. 88 9. 87

2 gutynyl triethylammonium chlori e.

t-(N-phenylcarbamoyloxy)-2-butenyl A 12. 66 12. 45

triemthylammonlurn chloride.

4-[N-(3-chlorophenyl)carbamoyloxyl- A 11. 20 11.11

2:3utenyl trimethylammonium 01110- n e.

4-[N-(3-ehlorophenyl)carbamoyloxyl- A 11. 41 11.21

butyl trirnethylammonium chloride.

1-carbamoyloxy-2-butynyl-4-trimethyl- A 1G. 63 17.16

ammonium chloride.

4-[N-(3-chlorophenyl)carbaxnoyloxy} A, C 52. 5 53.0 Zfiyutynyl trimethylamrnonium chlo- A,H 6. 1 5. 7 n e.

l-fN-( l-chlorophenyl) carbarnoyloxyl- A, O 52. 82 53. 0 2 l11utynyl triznethylarnxnoninm chlo- A, H 5. 5 5. 7 r1 e.

4-[N-(3-ohlorophenyl)earbamoyloxyl- D, percent 29.0 30. 9

i231 1;ynyldimethylammonium I.

o I e.

4-[N-(3-triflu0romethylphenyl) car- A, I Cl 10. 5 10.1

bamoyloxy -2-butynyltrimethyl ammonium chloride.

4[N-(a-naphthyl) carbamoyloxy]-2- A, I 01 10. 2 10. 6

butynyltrimethylammonium ch10 ride.

What is claimed is:

1. The compound 4-[-(Z-chlorophenyl)carbamoyloxy]- Z-butynyl tnimethylammonium chloride.

2. The compound 4 [N-(Z-chlorophenyhcarbamoyioxy] -2-butynyl triethylamrnonium bromide.

3. The compound 4- [N-(3-chlorophenyl)carbamoyloxy] -2-butynyldiethylmethy-lammonium iodide.

4. The compound 4- [N-(4-chlor-ophenyl) carbamoyloxy]-Z-butynyl triethylammonium chloride.

5. The compound 4- [N-(3-chlorophenyl)carbamoyloxy]-21bu tynyl tributylammonium chloride.

6. The compound 4- [N-(3-chloropheny1)carbamoyloxy]-2-butyny1 triethylammonium chloride.

7. The compound 1-carbamoyloxy2-butynyl-4-trimethylammoniumchloride.

8. The compound 4- [N-(3-chlorophenyl)carbamoyloxy] 42-butynyl trimethylammonium chloride.

9. The compound 4- [N-(4-chlorophenyl(carbamoyloxy] -2-butynyl trimethylammonium chloride.

10. The compound 4-[N-(3-chlorophenyl)carban1oyloxy]-2-butynyldimethylethylam-monium iodide.

11. The compound 4 [N (3 trifluoromethylphenyl) oarbamoyloxy] -2-butynyltrimethylammonium chloride.

12. The compound 4-[N-(a-naphthyncarbamoyloxfl- Z-butynyltrimethyl ammonium chloride.

References Cited in the file of this patent UNITED STATES PATENTS 1,894,162 Dalmer et al J an. 10, 1933 2,772,289 Cusic Nov. 27, 1956 2,794,810 Cusic June 4, 1957 2,967,880 Finke et a1 Jan. 10, 1961 2,973,385 Rorig Feb. 28, 1961 FOREIGN PATENTS 734,745 Great Britain Aug. 3, 1955 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,100,223 August 6, 1963 Thomas Robert Hopkins et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 60 for "loweding" read lowering column 3, line '74, for "C H CHN O read C H C1IN O column 4, line 40, after the opening bracket insert N Signed and sealed this 11th day of February 1964.

(SEAL) Attest:

ERNEST W. SWIDER EDWIN L. REYNOLDS Attesting Officer AC L 9 Commissioner of Patents 

1. THE COMPOUND 4-(-(2-CHLOROPHENYL)CARBAMOLYXYL)2-BUTYNYL TRIMETHYLAMMONIUM CHLORIDE.
 7. THE COMPOUND 1-CARBAMYLOXY-2-BUTYNYL-4-TRIMETHYLAMMONIUM CHLORIDE.
 12. THE COMPOUND 4-(N-(A-NAPHTYL0)CARBAMOYLOXY)2-BUTYNYLTRIMETHYLAMMONIUM CHLORIDE. 